Anti-inflammatory Benefits of Androstenetriol (b-AET)

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Anti-inflammatory Benefits of Androstenetriol (b-AET)

Androstene-3 beta-7 beta-17 beta-triol (AET) represents a key naturally occurring 7-hydroxy dehydroepiandrosterone (DHEA) metabolite. Produced from the adrenal gland, DHEA and its sulfate are the major circulating adrenal steroids in humans. Serum levels peak in young adults, but then steadily decline with age, falling over 80% by age 70. DHEA serves as a precursor of male and female sex hormones. (1, 3, 5, 6)


DHEA demonstrates a plethora of anti-aging properties in rodents, including anti-inflammatory, anti-obesity, anti-diabetic, immune enhancing activities, and opposes certain activities of endogenous glucocorticoids (GC). As the literature grew, DHEA became widely used as an anti-aging, anti-stress dietary supplement. Despite these well-documented activities in animal models, DHEA supplementation in humans has yielded inconclusive results and the value of DHEA replacement in humans is controversial. Such widely different outcomes in rodents and humans have been referred to as ‘the DHEA conundrum’. Moreover, the potential therapeutic use of DHEA is limited by its side effects due to its conversion to sex hormones.


One possibility to explain these discrepancies is that a metabolite(s) of DHEA, rather than DHEA itself, may be necessary for its full action in human physiology. DHEA undergoes extensive conversion and derivatization to multiple products by phase 1 reactions involving the cytochrome P450 system, and studies have shown that these phase 1 products can be more potent than parental DHEA. Phase 1 reactions frequently decline in elderly subjects, and since such subjects have been the major participants in human DHEA treatment studies, it is possible that biologically active metabolites of DHEA were not produced in adequate amounts in previous human studies. It is also possible that qualitative changes in DHEA metabolism between rodents and humans will account for these differences.


DHEA oxidation via the action of the enzyme CYP7B leads to the 7-hydroxy derivatives of C-19 steroids, which are collectively present in low nanomolar concentrations in human circulation and are not readily metabolized to potent androgens or estrogens. Many of the functions initially attributed to DHEA from observations in rodents are now thought to be properties of these oxygenated metabolites, particularly AET.

Molecular Structure of Androstenetriol

AET possesses some of the anti-inflammatory and GC-opposing activities that have been attributed to DHEA, but with greater apparent potency. Studies with AET demonstrate it markedly up regulates host immune response, prevents immune suppression, modulates inflammation and improves survival after lethal infections by pathogens and lethal radiation. (1, 3, 5, 6)


AET has been shown to be protective against traumatic shock. Traumatic shock activates the hypothalamic-pituitary-adrenal axis (HPA) to mediate a cascade of defensive mechanisms that often include overwhelming inflammatory response and immunosuppression, which may lead to multiple organ failure. In a relevant traumatic hemorrhagic shock rodent model that applies to both combat and civilian sectors, AET provided a significant protective effect and improved survival. In a murine thermal injury model that includes glucocorticoid-induced osteopenia, AET significantly preserved bone mineral content, restored whole body bone mineral content and bone growth, suggesting reversal of GC-mediated adverse effects.

Since AET is a naturally occurring compound there is no patent protection leaving the door wide open for AET analogue research. Harbor BioSciences, Inc. – (Public, OTC:HRBR – ) is exploring a synthetic derivative of AET for the treatment of diseases with underlying chronic inflammation. HRBR has developed 17alpha-Ethynyl-5-androsten-3beta, 7beta, 17beta-triol (HE3286), a synthetic derivative AET. (1, 2, 4, 7)

Within the past two years, animal model studies of HE3286 successfully demonstrate the treatment of lung inflammation without immune suppression, the reduction of established disease of rheumatoid arthritis, and both glucose-lowering and cholesterol-lowering effects. Harbor BioSciences most ambitious project to date is their recently released data regarding that plasma levels of AET positively correlate with BMI in healthy men and women.(1) These observations suggest a compensatory role for AET in preventing the development of metabolic syndrome and obesity. The AET structural core may provide the basis for novel pharmaceuticals to treat this disease, HE3286. Stay tuned.


1. Auci DL, Ahlem CN, Kennedy MR, Page TM, Reading CL, Frincke JM. A Potential Role for 5-Androstene-3[beta],7[beta],17[beta]-triol in Obesity and Metabolic Syndrome. Obesity.


2. Conrad D, Wang A, Pieters R, et al. HE3286, an oral synthetic steroid, treats lung inflammation in mice without immune suppression. Journal of Inflammation 2010;7(1):52.


3. Loria RM. Antiglucocorticoid function of androstenetriol. Psychoneuroendocrinology 1997;22 Suppl 1:S103-8.


4. Lu M, Patsouris D, Li P, et al. A new antidiabetic compound attenuates inflammation and insulin resistance in Zucker diabetic fatty rats. American Journal of Physiology – Endocrinology And Metabolism 2010;298(5):E1036-E48.


5. Malik AK, Khaldoyanidi S, Auci DL, et al. 5-androstene-3?,7?,17?-triol (?-AET) Slows Thermal Injury Induced Osteopenia in Mice: Relation to Aging and Osteoporosis. PLoS ONE;5(10):e13566.


6. Marcu AC, Paccione KE, Barbee RW, et al. Androstenetriol Immunomodulation Improves Survival in a Severe Trauma Hemorrhage Shock Model. The Journal of Trauma 2007;63(3):662-9.


7. Offner H, Firestein GS, Boyle DL, et al. An Orally Bioavailable Synthetic Analog of an Active Dehydroepiandrosterone Metabolite Reduces Established Disease in Rodent Models of Rheumatoid Arthritis. Journal of Pharmacology and Experimental Therapeutics 2009;329(3):1100-9.


8. Stiles AR, McDonald JG, Bauman DR, Russell DW. CYP7B1: One Cytochrome P450, Two Human Genetic Diseases, and Multiple Physiological Functions. Journal of Biological Chemistry 2009;284(42):28485-9.